Next Article in Journal
Validating EEG, MEG and Combined MEG and EEG Beamforming for an Estimation of the Epileptogenic Zone in Focal Cortical Dysplasia
Previous Article in Journal
Therapeutic Effects of a Newly Developed 3D Magnetic Finger Rehabilitation Device in Subacute Stroke Patients: A Pilot Study
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Brain Sciences
Volume 12
Issue 1
10.3390/brainsci12010112
brainsci-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Revisiting Hemispheric Asymmetry in Mood Regulation: Implications for rTMS for Major Depressive Disorder

by
Benjamin C. Gibson
1,2,
Andrei Vakhtin
2,
Vincent P. Clark
1,2,*,
Christopher C. Abbott
3 and
Davin K. Quinn
3
1
Psychology Clinical Neuroscience Center, University of New Mexico Psychology Department, Logan Hall, MSC03-2220, 1 University of New Mexico, Albuquerque, NM 87131, USA
2
The Mind Research Network/Lovelace Biomedical and Environmental Research Institute, 1101 Yale Blvd. NE, Albuquerque, NM 87106, USA
3
Department of Psychiatry and Behavioral Sciences, University of New Mexico School of Medicine, 2600 Marble Avenue NE, Albuquerque, NM 87106, USA
*
Author to whom correspondence should be addressed.
Brain Sci. 2022, 12(1), 112; https://doi.org/10.3390/brainsci12010112
Submission received: 8 December 2021 / Revised: 10 January 2022 / Accepted: 11 January 2022 / Published: 14 January 2022
(This article belongs to the Section Neuropsychiatry)
Versions Notes

Abstract

:
Hemispheric differences in emotional processing have been observed for over half a century, leading to multiple theories classifying differing roles for the right and left hemisphere in emotional processing. Conventional acceptance of these theories has had lasting clinical implications for the treatment of mood disorders. The theory that the left hemisphere is broadly associated with positively valenced emotions, while the right hemisphere is broadly associated with negatively valenced emotions, drove the initial application of repetitive transcranial magnetic stimulation (rTMS) for the treatment of major depressive disorder (MDD). Subsequent rTMS research has led to improved response rates while adhering to the same initial paradigm of administering excitatory rTMS to the left prefrontal cortex (PFC) and inhibitory rTMS to the right PFC. However, accumulating evidence points to greater similarities in emotional regulation between the hemispheres than previously theorized, with potential implications for how rTMS for MDD may be delivered and optimized in the near future. This review will catalog the range of measurement modalities that have been used to explore and describe hemispheric differences, and highlight evidence that updates and advances knowledge of TMS targeting and parameter selection. Future directions for research are proposed that may advance precision medicine and improve efficacy of TMS for MDD.

1. Introduction

The implications of hemispheric laterality have been of interest to neuroscientists and the lay public alike for over half a century [1]. During that time, research has identified hemispheric differences with respect to cognitive function [2], biological sex [3], age group [4], and importantly, emotional processing [5,6,7]. More recently, the conceptualization of hemispheric emotional processing differences has informed the treatment of mood disorders and the application of noninvasive brain stimulation through techniques such as repetitive transcranial magnetic stimulation (rTMS). Initial rTMS studies for MDD found beneficial group effects when applying excitatory high-frequency rTMS (HF-rTMS) to the left dorsolateral prefrontal cortex (DLPFC) [8], and inhibitory low-frequency rTMS (LF-rTMS) to the right DLPFC [9]. This paradigm quickly became standard clinical convention [10], a status it has retained to date [11,12].
Despite numerous studies confirming that the left DLPFC is an efficacious target for HF-rTMS at the group level, response rates with these protocols remain between 25% and 45% [11,12,13], and a recent large controlled trial with negative results have led to questions about the generalizability of this approach [14]. Precision medicine strategies have demonstrated the potential to improve response rates when delivered to the left DLPFC [15]. These new strategies have been facilitated by advances in neuronavigation and individualized targeting [16,17], and by advances in rTMS application, specifically the advent of the intermittent theta burst stimulation (iTBS) paradigm [18], capable of greatly reducing the required treatment time and increasing the viability of clinical application [19].
Despite these advances, one-third to one-half of patients still do not respond to rTMS [20]. Given that patients who receive rTMS have often failed “first line” treatments for MDD like psychopharmacology [21], a response rate of 50% following rTMS among this population should not be disregarded, but the exploration of novel rTMS protocols might allow for even further improvement. While a selective review of studies beyond the rTMS literature provides ample support for the conventional hemispheric paradigm [22], in consideration of the ongoing problem of treatment resistance in major depressive disorder (MDD) it is reasonable to ask whether treatment delivered outside the typical paradigm may benefit patients who do not response to rTMS. Evidence for this possibility exists, as the neuroscientific literature is more equivocal than might be expected based on the focus of rTMS and MDD research to date, with theoretical and experimental work providing a rationale for reconsideration of early protocols and exploration of novel protocols, particularly in the right hemisphere.
The purpose of this scoping narrative review is to assess the prevailing theories of hemispheric differences in emotion processing across studies examining lesion location, electroencephalography, split-brain function, and structural and functional neuroimaging. Original search terms included, hemispheric asymmetry, emotional lateralization, hemispheric specialization, valence hypothesis. Additional search terms and relevant citations were gleaned from theoretical reviews of hemispheric differences in emotion processing [5,7,23], and reviews of rTMS in MDD and MDD neuroscience. Considerations for rTMS treatment research that incorporate an updated conceptualization of hemispheric similarities and differences for MDD treatment are proposed.

2. Specialization vs. Valence

Two main theories have been proposed for right and left hemispheric differences in emotion processing. The first theory, hemispheric specialization, posits emotional processing as occurring predominantly in the right hemisphere, both for positive and negative emotions. A variant of this theory states that all initial emotional processing happens in the right hemisphere before being transferred to the left hemisphere for higher order appraisal and control [24,25,26]. The second theory posits the hemispheres as having divergent roles that depend upon the valence of a given emotion, where the right hemisphere is the processor of negative emotions and the left of positive emotions. A variant of this theory replaces positive and negative valence with approach (left hemisphere) and withdrawal (right hemisphere), making it consistent with findings associating anger generation with the left hemisphere [27,28,29], and anxiety generation in the right hemisphere [30,31], though both may be represented in diverse regions across the brain [32,33].
The field of noninvasive brain stimulation has tracked in line with the latter theory, following the observation that HF- and LF-rTMS are able to exert opposite effects on cortical excitability and neuronal metabolism [34,35,36]. Extensive work by Mayberg and others [37,38] demonstrating that hypometabolism/hypoactivity in the left frontal cortex was associated with depression provided the rationale for the first applications of HF-rTMS to the left DLPFC [8,39,40] and LF-rTMS to the right DLPFC [9,41,42]. Pascual-Leone’s 1996 study was the first evidence that the right hemisphere might respond oppositely to HF-rTMS compared to the left [8], setting the stage for numerous efficacy studies validating the left/excitatory, right/inhibitory paradigm [43].

2.1. Lesion Studies

Lesion studies form a relevant evidential base for understanding hemispheric differences as they pertain to rTMS application in MDD, as both single-pulse and repetitive TMS have been conceptualized as methods for generating virtual, temporary lesions [44,45]. Temporary and broad lesion-like effects were induced following the injection of sodium amobarbital as part of epilepsy surgery preoperative planning to determine hemispheric dominance for language [46]. Injection into the left carotid artery leading to temporary inactivation of the left hemisphere prompted reports of depressed mood, while injection into the right carotid artery with inactivation of the right hemisphere prompted reports of euphoria [47,48,49]. These findings were in line with emotional changes seen with lesions following stroke, where a higher propensity for depression was observed following strokes that damaged areas of the anterior left hemisphere. In contrast, damage to the anterior right hemisphere was observed to lead to an elevated mood state [50,51,52]. A similar pattern was seen among multiple sclerosis patients, with those with MDD displaying greater white matter damage to the left PFC [53]. These emotional changes following lesioning are thought to not only reflect the direct effect of the lesion itself, but also to represent a “release” of the unaffected side through loss of transcallosal inhibitory effects from the lesioned hemisphere [54,55].
In recent years, however, reviews have found mixed evidence in support of the connection between lesion location and depression [56], with some finding that right hemisphere lesions, rather than left, were more often associated with depression several months following stroke [57]. This was echoed in a recent meta-analysis that also found differences in the likelihood of depression in different periods following stroke damage, where right hemisphere lesions were associated with depression during the subacute phase immediately following a stroke, but after 6 months this association no longer held [58]. In contrast, another recent review found that lesions in the left hemisphere were more often associated with depression in the acute phase (1–3 months) following stroke, and that females displayed a greater likelihood of reporting depression with left hemisphere lesions [59]. Moderating factors such as sex are often at play in hemispheric differences between emotional processing and the manifestation of depression. Furthermore, consistent with a shifting conceptualization of MDD as a disorder of brain networks rather than brain regions [60,61,62,63], recent evidence suggests that the hemispheric location is less important than the alterations in the functional connectivity of large-scale networks that accompany lesions in specific cortical regions on either side [54].

2.2. Interoperative Brain Stimulation

For those receiving brain surgery for tumor removal, interoperative mapping of the brain through direct electrical stimulation is vital for maintaining critical functions following recovery. This includes the mapping of emotional appraisal [64]. Similarly, the implanting of intracranial electrodes is used in patients with intractable epilepsy to determine the epicenter of seizure activity prior to surgical intervention [65]. As a result of these interventions, researchers have been able to directly study brain regions and fiber tracts vital for emotional appraisal. Research from this area offers compelling evidence that the assessment of the emotional experience of others is a function of the right hemisphere [66,67]. In particular, the identification of emotional facial expressions in others involves cortical structures in the right hemisphere [68,69], a process that is distinct from the identification of faces generally [70]. Yet, while it is likely that emotional appraisal is centered in the right hemisphere, the experience of emotion itself is likely more diffuse. In an interoperative surgery case study, stimulating the cingulum bundle medial and inferior to the right superior temporal gyrus caused smiling and laughter, but in the absence of any underlying mirth [71]. In contrast, direct stimulation of the left anterior cingulum bundle elicited both smiling and laughter in additional to a positive emotional experience [72]. While it is likely that the exact location for eliciting mirth has heterogeneity across individuals [73], these targets are approaching those that have been suggested for deep brain stimulation for MDD [74], as well as recently proposed anticorrelated targets for rTMS [75].

2.3. Perceptual/Split-Brain Studies

Hemispheric differences in emotional processing have been explored in healthy adults through the dichotic listening and visual hemifield paradigms, together known as perceptual asymmetry. Dichotic listening tests involve simultaneous presentation of different auditory stimuli to both the left and right ear. A left ear/right hemisphere advantage is typically shown for the processing of emotional and nonverbal stimuli, while a right ear/left hemisphere advantage is shown for non-emotional and verbal stimuli [76]. Patients with mood disorders show evidence of hemispheric dysfunction in the dichotic listening paradigm, though the direction of this dysfunction varies, with those with anxiety disorders displaying worse performance for verbal stimuli (evidence for an underperforming left hemisphere), and those with MDD displaying worse performance for non-verbal stimuli (evidence for an underperforming right hemisphere) [77,78,79]. A similar pattern is seen in studies presenting lateralized visual stimuli, with those diagnosed with MDD having a reduced left hemi-spatial bias, and those with anxiety an increased bias [80]. Additionally, perceptual asymmetry differences are seen among subtypes of MDD, where a right hemispheric bias is observed in those with atypical MDD and dysthymia but not in those with MDD and melancholia [81]. Sex is also a moderating factor in perceptual asymmetry, with those with MDD demonstrating a reduced right hemisphere advantage for auditory stimuli that is more apparent among males [23].
Studies in patients who have had the corpus callosum severed, so-called “split-brain” patients, are complementary to those seen in perceptual asymmetry. The case of patient VP, as studied by Gazzaniga and Le Doux, provided an account of the emotional processing each hemisphere was uniquely capable of when VP was presented with stimuli to only the left or right hemisphere. When a frightening scene was presented to the right hemisphere’s visual field, VP was able to correctly identify the cause of the ensuing physiological arousal. However, when such a scene was presented to the left hemisphere, VP ascribed it to the unnerving nature of the room rather than the presented stimuli, suggesting that VP’s verbal left hemisphere was unable to accurately identify the cause of physiological change in the absence of communication from the right hemisphere [82]. Split-brain patients have also demonstrated poor recognition of emotional facial expressions presented to the left hemisphere, but good recognition when presented to the right [83], with the same relationship evident when interpreting emotionally laden written material [84] and when verbalizing emotion [85,86]. One interpretation of split brain studies is that the left hemisphere is able to make an interpretive best guess, but lacks the emotional comprehension provided by the right hemisphere [87]. Thus, split brain findings seem to support the idea that the majority of emotional appraisal, both positive and negative, occurs in the right hemisphere, rather than being distributed across the hemispheres according to valence or approach [5,88].

2.4. Electroencephalography Studies

In electroencephalography (EEG) studies, the relationship between the left and right PFC has been measured with frontal alpha asymmetry (FAA). According with behavioral results for perceptual asymmetry studies, FAA differences have been detected across patients with different mood disorder symptom profiles, with reduced activity observed over the left PFC in those diagnosed with MDD [30,89], and anxious apprehension associated with reduced activity in the right PFC compared to those with anhedonia [90]. This potential ability to identify subtypes of affective disorder as well as an ability to diagnose MDD led to efforts to use FAA as a diagnostic tool [91]. However, a recent meta-analysis found FAA had no diagnostic utility, at least in younger and middle aged adults [92]. In older adults (>53 years old) an interaction was observed in females diagnosed with MDD who presented with right-sided FAA, indicating greater cortical functionality in the left PFC compared to the right, while older males with MDD displayed left-sided FAA. In order to identify further actionable differences, it is likely that higher density EEG recording montages are needed, as treating the right and left PFC as functional units has often been due to measurement constraint rather than theoretical approach [6,93]. Even this may not prove sufficient, as FAA was not detected in a sample of 1008 MDD patients [94], despite performance of additional aggregative analyses [95].

2.5. Volumetric Studies

Examinations of brain volume changes reveal hemispheric differences related to mood disorder symptom profiles. Van Tol and colleagues observed that those with MDD unaccompanied by comorbid anxiety disorders had reduced brain volume in the right ventrolateral PFC (VLPFC) [96], a result that was subsequently supported in a meta-analysis of grey matter changes in MDD, where reductions across the right PFC were observed in MDD patients without comorbid anxiety [97]. However, the finding of reduced right VLPFC [98] and bilateral inferior frontal gyrus (IFG) [99] grey matter in those with anxious MDD has also been seen. Grey matter changes in the right superior frontal gyrus have also been shown to correlate with antidepressant medication treatment outcome, where treatment responders had higher, and treatment non-responders lower, grey matter volumes compared to controls [100]. Increases in grey matter volume have been seen following rTMS application for MDD, with subsequent symptom improvement correlated with volume increases in the anterior cingulate [101,102], a brain region implicated in multiple cognitive and emotional systems [103]. However, increases in cingulate cortex volume following rTMS coupled with an absence of clinical effects has also been observed [104], indicating that neuroplasticity changes alone may not be sufficient for symptom improvement, or that neuroplasticity changes may precede symptom improvement. Future research is needed, but grey matter volume may be a promising modality for measuring MDD subtypes and the effectiveness of rTMS interventions [105].

2.6. Molecular and Nuclear Imaging Studies

Early positron emission tomography (PET) studies found impaired left PFC metabolism in those with MDD [106], and improvements in this area were associated with positive treatment outcomes [107,108]. In the right PFC, both hypo- and hyperactivity have been demonstrated in patients with MDD [109,110]. In an early attempt at individualized precision medicine, Herwig and colleagues applied HF-rTMS to either the right or left DLPFC with the hemisphere of application determined by the side with more prominent hypometabolism as measured by PET. In most patients, the right hemisphere was identified as more hypometabolic. While a 30% reduction was seen in those who received left and right DLPFC rTMS, three patients receiving left DLFPC stimulation saw a 50% improvement in symptoms, compared to only one with right DLPFC stimulation [111] and overall the study did not improve on typical response rates [112]. A subsequent study used a similar design, with PET hypometabolism guiding HF-rTMS placement in 30 patients with left-sided hypometabolism and 16 with right-sided. Left sided stimulation was again superior at the group level, and in 7 of 16 receiving right-sided stimulation, only two displayed greater than 50% improvement in depression scores [113]. Based on these results, a generic approach would call for left-sided stimulation, but this runs the risk of ignoring a significant proportion of patients who benefit from right-sided HF-rTMS, possibly due to specific symptom profiles. In a single photon emission computed tomography study measuring blood flow rather than neuronal metabolism, those with melancholic MDD displayed a decrease in blood flow to both the left and right frontal lobes, while an increase in blood flow to the right frontal lobe was seen in patients with atypical MDD featuring symptoms such as increased appetite, sleep, and weight gain [114], highlighting the ongoing importance of determining how clinical profiles may influence rTMS efficacy [60].

2.7. White Matter Studies

Disruptions in white matter integrity have been observed in those with MDD, with white matter disruptions in the right hemisphere more widespread than those in the left [115]. In a recent study applying machine learning to diffusion tensor imaging (DTI) in patients with MDD and controls, a model containing fractional anisotropy maps of the right hemisphere alone was most successful in separating patients from controls, identifying those with MDD with 80% accuracy [116]. Other studies have implicated DTI findings in the corpus callosum, indicating that MDD may involve impaired hemispheric communication [116,117], though it is unclear whether this impairment is functional, structural, or both [118,119,120]. Adding further complexity to this picture, a study combining resting state functional connectivity MRI (rsfMRI) and DTI found that changes in the functional and structural coupling of intra-hemispheric communication correlated with depression severity, where greater depression severity was associated with greater functional-structural coupling [120]. Importantly, rTMS has demonstrated an ability to affect white matter tracts within the stimulated hemisphere [121,122]. Recent studies have demonstrated hemispheric differences in white matter topography underlying key cortical areas involved in mood and anxiety regulation [123,124,125], further suggesting that differences in structural connectivity between the left and right hemispheres in MDD likely have bearing on the efficacy of rTMS. This may be especially true in older adults, where it has been proposed that MDD is the result of age related degradation of white matter tracts [126].

2.8. Task-Related fMRI

Several task-related functional magnetic resonance imaging (fMRI) studies have provided support for a version of the valence model, indicating a hypoactive left PFC and a hyperactive right PFC during an emotion induction task in those diagnosed with MDD [127,128,129]. In contrast, other studies have found that depressed patients demonstrate a hypoactive right PFC compared to controls during emotion induction [128,130,131], coupled with left PFC hyperactivity [127]. This heterogeneity is summarized in a meta-analysis of task-based activation studies where no brain regions emerged as significantly different in those with MDD compared to controls across 99 neuroimaging experiments [132]. In addition to experimental differences in stimuli and analysis, differences in age, sex, medication status, and MDD subtypes likely also lead to contrasting results. In one interesting task-based study that accounted for subtypes of MDD, those with high anxious arousal and low anxious apprehension demonstrated increased activity in the right DLPFC and reduced activity in the right VLPFC [133]. This difference across types of symptom profiles may help explain contrasting results seen in other measurement modalities, such as in grey matter and PET changes in the right PFC, and points toward emerging work suggesting that variable activity at specific depression network nodes is likely to underlie different symptoms [60].

2.9. Functional Connectivity fMRI Studies

Of the imaging modalities included in this review, rsfMRI has played the largest role in advancing precision medicine applications of rTMS in MDD over the last decade. Building on evidence indicating that alterations in the subgenual anterior cingulate cortex (sgACC) provide a meaningful biomarker in MDD [134,135], Fox and colleagues assessed whether rTMS efficacy could be predicted by examining functional connectivity between the left DLFPC and sgACC. They found that DLPFC stimulation sites with greater anticorrelation with the sgACC were more effective targets, with the degree of anticorrelation accounting for 70% of the variance in treatment outcome [136]. The viability of this method for improving personalized targeting has since been replicated, improving treatment response rates to between 44% and 90% [137,138,139,140], a significant improvement over response rates seen in earlier treatment studies of rTMS for MDD.
Despite this improvement, it is likely that a significant proportion of non-responders to left DLPFC stimulation may still benefit from rTMS, as indicated by the PET studies which found that a small number of subjects responded dramatically to HF-rTMS delivered to the right PFC [111,113]. Such a possibility fits with the finding that over 1000 unique symptom profiles are possible in MDD [141]. Work identifying the HF-rTMS right PFC symptom profile has begun [142], and emerging evidence suggests that, similar to findings with other experimental paradigms, comorbid anxiety alters resting state functional connectivity (rsFC) to the right PFC, with altered connectivity between right VLPFC and limbic system in patients with comorbid anxiety compared to those with MDD only [143]. In an intriguing directed functional connectivity analysis, a subgroup with anxiety, recurrent MDD and greater female representation displayed effective connectivity emanating from the VLPFC to the right parietal lobe [144]. Similarly, patients divided into anxiosomatic and dysphoric depression subtypes had contrasting PFC targets, with anxiosomatic symptoms responding more avidly to posteromedial rTMS treatment targets, and dysphoric patients having targets in both hemispheres more anterolateral to targets derived from traditional DLPFC targeting [145]. In a large study using data from over 1000 subjects, MDD subtypes were delineated based on rsFC [60] with a single biotype loading on fatigue and anergia most strongly associated with the right ventrolateral PFC with concurrent reduced connectivity to the anterior cingulate. In an important test of their approach, HF-rTMS targeting the DMPFC of patients in each of four identified biotypes resulted in significantly contrasting response rates. Those classified as biotype 1, with a symptom profile of fatigue/anergia, middle insomnia, and anxiety responded at a rate of 82.5% (greater than 25% reduction in depression scores) compared to a response rate of 61%, 25% and 29.6% for the other three biotypes. Given these findings of specific symptoms responding better to specific placements, we expect that the connectivity phenotypes observed in rsFC studies such as by Drysdale et al. may indicate a differential responsivity to stimulation across targets, such as the DLPFC or DMPFC.
Finally, Siddiqi et al. in 2021 published a cross-cutting study of combined rsfMRI data from eight heterogeneous studies examining connectivity changes associated with post-stroke MDD, rTMS for MDD, and deep brain stimulation for MDD [63]. A common depression network was revealed that partially overlaps with the executive and salience networks, with correlation between nodes in the inferior frontal gyrus (IFG), DLPFC, dorsal ACC, and posterior parietal cortex (PPC), and anticorrelation with the default mode network and nodes in the subgenual cingulate cortex and ventromedial prefrontal cortex. While this study lends support to the approaches of targeting rTMS that have succeeded thus far, namely, to target the DMPFC, the DLPFC, and even the IFG, what is noteworthy in this study from a laterality perspective is the symmetry of network topography between the left and right hemispheres, which argues against a lateralization of emotional regulation. If the important treatment targets for rTMS are bilaterally distributed network nodes, then the location of stimulation should be determined by which nodes offer the most efficacious ingress point for influencing important subcortical structures such as the amygdala [146], PCC [125], and sgACC. It is possible that indirect stimulation of the sgACC may be best achieved through nodes in the right hemisphere, which have potentially more robust connections through the anterior insula to the sgACC and function critically as part of the central executive and salience networks [147,148,149]. Please refer to Table 1 for a brief summary of reviewed findings.

3. Implications for rTMS for MDD

While this paper began by reviewing theories of hemispheric emotional processing differences, it is possible that thinking in terms of hemispheric differences represents a binary fallacy, more representative of how humans think than of the actual structure and function of the human brain. Hemispheric lateralization in various domains of cognition, emotional processing, personality, and behavior selection has become a common allusion in mainstream Western society (e.g., “left-brain” versus “right-brain” people), and clinical researchers are not immune to the allure of an elegant binary formulation, particular if it is associated with clinical treatment paradigms. Influential findings in early lesion studies and split-brain studies provided the initial empirical bases for theorized differences in hemispheric function, with follow-up studies using sophisticated imaging techniques such as EEG, structural and functional MRI, and PET describing a more complex and qualified picture of hemispheric brain function, particularly through the valence theory of emotional processing. The behavioral effects in multiple studies of rTMS for MDD based on these principles of hemispheric lateralization have largely conformed to expectations, with far fewer studies having been conducted to provide counter evidence to this theory (e.g., right/excitatory, left/inhibitory).
However, evidence against the “restoration” of a beneficial or optimal balance between the left and right hemispheres concurrent with the alleviation of MDD through the left/excitatory, right/inhibitory stimulation paradigm is starting to emerge. First, imaging studies of rTMS effects in MDD demonstrate changes in network interactions that can span both hemispheres [150], and through recent rsfMRI studies a bilateral depression network appears to be coalescing with symmetric nodes in the left and right hemispheres [63]. Dynamics between these bilateral networks, such as the executive, salience, and default mode networks, appear to be more relevant than the dynamics between left and right hemisphere, both for MDD [151] and psychopathology broadly [62]. Second, excitatory stimulation patterns to the right hemisphere, such as 10Hz HF-rTMS and intermittent theta burst stimulation (iTBS) can also have antidepressant effects [142,152,153,154], indicating that contrary earlier findings may not have undergone sufficiently rigorous confirmation. Through the study of stimulation paradigms symmetrically across both hemispheres, it will be possible to understand how the hemispheres innately function in emotion processing and mood regulation. For instance, it is widely believed that anxiety may be a symptom emanating more from right hemisphere activity, and that treatment directed at the right hemisphere can have anxiolytic effects [155,156,157]. With excitatory patterns being applied to the right hemisphere, it will be possible to quantify to what degree anxiogenesis or anxiolysis may occur in comparison to the left hemisphere. Third, clinical anecdote and naturalistic studies indicate that hemispheric lateralization may occur more at the level of the patient rather than at the population level, with specific individuals having variable levels of depression network plasticity in a given hemisphere, suggesting that antidepressant brain stimulation for a given patient will need to be directed to either the left, right, or both hemispheres based on their specific network activity.
The increasing use of symmetric protocols (where the same parameters are applied to both sides of the brain) will allow for an understanding of these differences. This is not to suggest that the field should abandon inhibitory protocols, as many patients have seen successful remission of MDD with 1 Hz stimulation; rather, we suggest that the personalization of rTMS will need to include laterality as one of at least four levels of personalization: (1) identification of target locations through functional connectivity studies, such as the sgACC-DLPFC anticorrelated target; (2) identification and characterization of which anticorrelated network nodes are the optimal targets, such as the IFG, dorsal ACC, and PPC; (3) identification of how strongly the laterality of targets factors into clinical efficacy; (4) and identification of how stimulation parameters themselves vary in their effects depending on target location and laterality.
Improving the efficacy of MDD treatment will also likely entail the formulation of theories that are able to integrate various phenotypes seen in MDD subpopulations. Demographic and clinical features such as sex, age, and the presence of comorbid psychiatric disorders will undoubtedly play a role in guiding future research and determining optimal personalized treatment that accounts for comorbidities. A theoretical understanding of changes common to specific populations with lower response rates, such as interhemispheric reorganization of brain activity seen in aging [4,158], can help to guide subsequent individualized approaches within those populations. Recognition that the alluring binary of right versus left hemispheric differences in emotional processing is at best simplistic and at worst iatrogenic is a first step towards improving theoretical understanding and treatment outcomes following rTMS MDD treatment.

Author Contributions

Conceptualization, B.C.G. and D.K.Q.; Investigation, B.C.G. and D.K.Q.; Resources, D.K.Q.; Writing—Original Draft Preparation, B.C.G. and D.K.Q.; Writing—Review and Editing, all authors; Supervision, D.K.Q.; Project Administration, D.K.Q.; Funding Acquisition, D.K.Q. and V.P.C. All authors have read and agreed to the published version of the manuscript.

Funding

This Research was sponsored by grants from The National Institute of Health (P30GM122734).

Conflicts of Interest

VC is a Scientific Consultant for NeuroGeneces, Inc. The authors declare that they have no other conflicts of interest.

References

  1. McGilchrist, I. The Master and His Emissary; Yale University Press: London, UK, 2019; ISBN 978-030-024-745-9. [Google Scholar]
  2. Gotts, S.J.; Jo, H.J.; Wallace, G.L.; Saad, Z.S.; Cox, R.W.; Martin, A. Two Distinct Forms of Functional Lateralization in the Human Brain. Proc. Natl. Acad. Sci. USA 2013, 110, E3435–E3444. [Google Scholar] [CrossRef] [Green Version]
  3. Hirnstein, M.; Hugdahl, K.; Hausmann, M. Cognitive Sex Differences and Hemispheric Asymmetry: A Critical Review of 40 Years of Research. Laterality 2019, 24, 204–252. [Google Scholar] [CrossRef] [PubMed]
  4. Davis, S.W.; Kragel, J.E.; Madden, D.J.; Cabeza, R. The Architecture of Cross-Hemispheric Communication in the Aging Brain: Linking Behavior to Functional and Structural Connectivity. Cereb. Cortex 2012, 22, 232–242. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Gainotti, G. A Historical Review of Investigations on Laterality of Emotions in the Human Brain. J. Hist. Neurosci. 2019, 28, 23–41. [Google Scholar] [CrossRef]
  6. Miller, G.A.; Crocker, L.D.; Spielberg, J.M.; Infantolino, Z.P.; Heller, W. Issues in Localization of Brain Function: The Case of Lateralized Frontal Cortex in Cognition, Emotion, and Psychopathology. Front. Integr. Neurosci. 2013, 7, 2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Shobe, E.R. Independent and Collaborative Contributions of the Cerebral Hemispheres to Emotional Processing. Front. Hum. Neurosci. 2014, 8, 230. [Google Scholar] [CrossRef]
  8. Pascual-Leone, A.; Rubio, B.; Pallardó, F.; Catalá, M.D. Rapid-Rate Transcranial Magnetic Stimulation of Left Dorsolateral Prefrontal Cortex in Drug-Resistant Depression. Lancet 1996, 348, 233–237. [Google Scholar] [CrossRef]
  9. Feinsod, M.; Kreinin, B.; Chistyakov, A.; Klein, E. Preliminary Evidence for a Beneficial Effect of Low-Frequency, Repetitive Transcranial Magnetic Stimulation in Patients with Major Depression and Schizophrenia. Depress. Anxiety 1998, 7, 65–68. [Google Scholar] [CrossRef]
  10. Couturier, J.L. Efficacy of Rapid-Rate Repetitive Transcranial Magnetic Stimulation in the Treatment of Depression: A Systematic Review and Meta-Analysis. J. Psychiatry Neurosci. 2005, 30, 83–90. [Google Scholar]
  11. Berlim, M.; Eynde, F.; Tovar-Perdomo, S.; Daskalakis, Z. Response, Remission and Drop-out Rates Following High-Frequency Repetitive Transcranial Magnetic Stimulation (RTMS) for Treating Major Depression: A Systematic Review and Meta-Analysis of Randomized, Double-Blind and Sham-Controlled Trials. Psychol. Med. 2013, 44, 225–239. [Google Scholar] [CrossRef]
  12. Cao, X.; Deng, C.; Su, X.; Guo, Y. Response and Remission Rates Following High-Frequency vs. Low-Frequency Repetitive Transcranial Magnetic Stimulation (RTMS) Over Right DLPFC for Treating Major Depressive Disorder (MDD): A Meta-Analysis of Randomized, Double-Blind Trials. Front. Psychiatry 2018, 9, 413. [Google Scholar] [CrossRef]
  13. Chen, J.; Zhou, C.; Wu, B.; Wang, Y.; Li, Q.; Wei, Y.; Yang, D.; Mu, J.; Zhu, D.; Zou, D.; et al. Left versus Right Repetitive Transcranial Magnetic Stimulation in Treating Major Depression: A Meta-Analysis of Randomised Controlled Trials. Psychiatry Res. 2013, 210, 1260–1264. [Google Scholar] [CrossRef] [PubMed]
  14. Yesavage, J.A.; Fairchild, J.K.; Mi, Z.; Biswas, K.; Davis-Karim, A.; Phibbs, C.S.; Forman, S.D.; Thase, M.; Williams, L.M.; Etkin, A.; et al. Effect of Repetitive Transcranial Magnetic Stimulation on Treatment-Resistant Major Depression in US Veterans: A Randomized Clinical Trial. JAMA Psychiatry 2018, 75, 884–893. [Google Scholar] [CrossRef]
  15. Cocchi, L.; Zalesky, A. Personalized Transcranial Magnetic Stimulation in Psychiatry. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 2018, 3, 731–741. [Google Scholar] [CrossRef]
  16. Ahdab, R.; Ayache, S.S.; Brugières, P.; Goujon, C.; Lefaucheur, J.-P. Comparison of “Standard” and “Navigated” Procedures of TMS Coil Positioning over Motor, Premotor and Prefrontal Targets in Patients with Chronic Pain and Depression. Neurophysiol. Clin./Clin. Neurophysiol. 2010, 40, 27–36. [Google Scholar] [CrossRef] [PubMed]
  17. Baeken, C.; Duprat, R.; Wu, G.-R.; De Raedt, R.; van Heeringen, K. Subgenual Anterior Cingulate–Medial Orbitofrontal Functional Connectivity in Medication-Resistant Major Depression: A Neurobiological Marker for Accelerated Intermittent Theta Burst Stimulation Treatment? Biol. Psychiatry Cogn. Neurosci. Neuroimaging 2017, 2, 556–565. [Google Scholar] [CrossRef] [PubMed]
  18. Huang, Y.-Z.; Edwards, M.J.; Rounis, E.; Bhatia, K.P.; Rothwell, J.C. Theta Burst Stimulation of the Human Motor Cortex. Neuron 2005, 45, 201–206. [Google Scholar] [CrossRef] [Green Version]
  19. Blumberger, D.M.; Vila-Rodriguez, F.; Thorpe, K.E.; Feffer, K.; Noda, Y.; Giacobbe, P.; Knyahnytska, Y.; Kennedy, S.H.; Lam, R.W.; Daskalakis, Z.J.; et al. Effectiveness of Theta Burst versus High-Frequency Repetitive Transcranial Magnetic Stimulation in Patients with Depression (THREE-D): A Randomised Non-Inferiority Trial. Lancet 2018, 391, 1683–1692. [Google Scholar] [CrossRef]
  20. Cash, R.F.H.; Weigand, A.; Zalesky, A.; Siddiqi, S.H.; Downar, J.; Fitzgerald, P.B.; Fox, M.D. Using Brain Imaging to Improve Spatial Targeting of Transcranial Magnetic Stimulation for Depression. Biol. Psychiatry 2020, 90, 689–700. [Google Scholar] [CrossRef]
  21. Boes, A.D.; Kelly, M.S.; Trapp, N.T.; Stern, A.P.; Press, D.Z.; Pascual-Leone, A. Noninvasive Brain Stimulation: Challenges and Opportunities for a New Clinical Specialty. J. Neuropsychiatry Clin. Neurosci. 2018, 30, 173–179. [Google Scholar] [CrossRef]
  22. Hecht, D. Depression and the Hyperactive Right-Hemisphere. Neurosci. Res. 2010, 68, 77–87. [Google Scholar] [CrossRef] [PubMed]
  23. Bruder, G.E.; Stewart, J.W.; Hellerstein, D.; Alvarenga, J.E.; Alschuler, D.; McGrath, P.J. Right Brain, Left Brain in Depressive Disorders. Psychiatry Res. 2012, 196, 250–254. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Aftanas, L.I.; Varlamov, A.A. Effects of Alexithymia on the Activity of the Anterior and Posterior Areas of the Cortex of the Right Hemisphere in Positive and Negative Emotional Activation. Neurosci. Behav. Physiol. 2007, 37, 67–73. [Google Scholar] [CrossRef]
  25. Gainotti, G.; Caltagirone, C.; Zoccolotti, P. Left/Right and Cortical/Subcortical Dichotomies in the Neuropsychological Study of Human Emotions. Cogn. Emot. 1993, 7, 71–93. [Google Scholar] [CrossRef]
  26. Heller, W.; Nitschke, J.B.; Miller, G.A. Lateralization in Emotion and Emotional Disorders. Curr. Dir. Psychol. Sci. 1998, 7, 26–32. [Google Scholar] [CrossRef]
  27. Davidson, R.J. Anterior Cerebral Asymmetry and the Nature of Emotion. Brain Cogn. 1992, 20, 125–151. [Google Scholar] [CrossRef]
  28. Davidson, R.J.; Irwin, W. The Functional Neuroanatomy of Emotion and Affective Style. Trends Cogn. Sci. 1999, 3, 11–21. [Google Scholar] [CrossRef]
  29. Harmon-Jones, E.; Gable, P.A.; Peterson, C.K. The Role of Asymmetric Frontal Cortical Activity in Emotion-Related Phenomena: A Review and Update. Biol. Psychol. 2010, 84, 451–462. [Google Scholar] [CrossRef] [PubMed]
  30. Bruder, G.E.; Stewart, J.W.; McGrath, P.J. Right Brain, Left Brain in Depressive Disorders: Clinical and Theoretical Implications of Behavioral, Electrophysiological and Neuroimaging Findings. Neurosci. Biobehav. Rev. 2017, 78, 178–191. [Google Scholar] [CrossRef]
  31. Pizzagalli, D.A.; Nitschke, J.B.; Oakes, T.R.; Hendrick, A.M.; Horras, K.A.; Larson, C.L.; Abercrombie, H.C.; Schaefer, S.M.; Koger, J.V.; Benca, R.M.; et al. Brain Electrical Tomography in Depression: The Importance of Symptom Severity, Anxiety, and Melancholic Features. Biol. Psychiatry 2002, 52, 73–85. [Google Scholar] [CrossRef]
  32. Engels, A.S.; Heller, W.; Mohanty, A.; Herrington, J.D.; Banich, M.T.; Webb, A.G.; Miller, G.A. Specificity of Regional Brain Activity in Anxiety Types during Emotion Processing. Psychophysiology 2007, 44, 352–363. [Google Scholar] [CrossRef]
  33. Stewart, J.L.; Levin-Silton, R.; Sass, S.M.; Heller, W.; Miller, G.A. Anger Style, Psychopathology, and Regional Brain Activity. Emotion 2008, 8, 701–713. [Google Scholar] [CrossRef] [Green Version]
  34. Loo, C.K.; Sachdev, P.S.; Haindl, W.; Wen, W.; Mitchell, P.B.; Croker, V.M.; Malhi, G.S. High (15 Hz) and Low (1 Hz) Frequency Transcranial Magnetic Stimulation Have Different Acute Effects on Regional Cerebral Blood Flow in Depressed Patients. Psychol. Med. 2003, 33, 997–1006. [Google Scholar] [CrossRef] [PubMed]
  35. Speer, A.M.; Kimbrell, T.A.; Wassermann, E.M.; Repella, J.D.; Willis, M.W.; Herscovitch, P.; Post, R.M. Opposite Effects of High and Low Frequency RTMS on Regional Brain Activity in Depressed Patients. Biol. Psychiatry 2000, 48, 1133–1141. [Google Scholar] [CrossRef]
  36. Wassermann, E.M.; Wedegaertner, F.R.; Ziemann, U.; George, M.S.; Chen, R. Crossed Reduction of Human Motor Cortex Excitability by 1-Hz Transcranial Magnetic Stimulation. Neurosci. Lett. 1998, 250, 141–144. [Google Scholar] [CrossRef]
  37. Kennedy, S.H.; Evans, K.R.; Krüger, S.; Mayberg, H.S.; Meyer, J.H.; McCann, S.; Arifuzzman, A.I.; Houle, S.; Vaccarino, F.J. Changes in Regional Brain Glucose Metabolism Measured with Positron Emission Tomography after Paroxetine Treatment of Major Depression. Am. J. Psychiatry 2001, 158, 899–905. [Google Scholar] [CrossRef] [PubMed]
  38. Mayberg, H.S. Limbic-Cortical Dysregulation: A Proposed Model of Depression. J. Neuropsychiatry Clin. Neurosci. 1997, 9, 471–481. [Google Scholar] [CrossRef]
  39. George, M.S.; Wassermann, E.M.; Williams, W.A.; Callahan, A.; Ketter, T.A.; Basser, P.; Hallett, M.; Post, R.M. Daily Repetitive Transcranial Magnetic Stimulation (RTMS) Improves Mood in Depression. Neuroreport Int. J. Rapid Commun. Res. Neurosci. 1995, 6, 1853–1856. [Google Scholar] [CrossRef] [PubMed]
  40. Loo, C.; Mitchell, P.; Sachdev, P.; McDarmont, B.; Parker, G.; Gandevia, S. Double-Blind Controlled Investigation of Transcranial Magnetic Stimulation for the Treatment of Resistant Major Depression. Am. J. Psychiatry 1999, 156, 946–948. [Google Scholar] [CrossRef] [Green Version]
  41. Fitzgerald, P.B.; Brown, T.L.; Marston, N.A.U.; Daskalakis, Z.J.; de Castella, A.; Kulkarni, J. Transcranial Magnetic Stimulation in the Treatment of Depression: A Double-Blind, Placebo-Controlled Trial. Arch. Gen. Psychiatry 2003, 60, 1002–1008. [Google Scholar] [CrossRef] [Green Version]
  42. Klein, E.; Kreinin, I.; Chistyakov, A.; Koren, D.; Mecz, L.; Marmur, S.; Ben-Shachar, D.; Feinsod, M. Therapeutic Efficacy of Right Prefrontal Slow Repetitive Transcranial Magnetic Stimulation in Major Depression: A Double-Blind Controlled Study. Arch. Gen. Psychiatry 1999, 56, 315–320. [Google Scholar] [CrossRef] [Green Version]
  43. Mutz, J.; Edgcumbe, D.R.; Brunoni, A.R.; Fu, C.H.Y. Efficacy and Acceptability of Non-Invasive Brain Stimulation for the Treatment of Adult Unipolar and Bipolar Depression: A Systematic Review and Meta-Analysis of Randomised Sham-Controlled Trials. Neurosci. Biobehav. Rev. 2018, 92, 291–303. [Google Scholar] [CrossRef] [Green Version]
  44. George, M.S.; Ketter, T.A.; Post, R.M. Prefrontal Cortex Dysfunction in Clinical Depression. Depression 1994, 2, 59–72. [Google Scholar] [CrossRef]
  45. George, M.S.; Wassermann, E.M. Rapid-Rate Transcranial Magnetic Stimulation and ECT. Convuls. Ther. 1994, 10, 251–254. [Google Scholar] [PubMed]
  46. Baxendale, S. The Wada Test. Curr. Opin. Neurol. 2009, 22, 185–189. [Google Scholar] [CrossRef]
  47. Ahern, G.L.; Herring, A.M.; Tackenberg, J.N.; Schwartz, G.E.; Seeger, J.F.; Labiner, D.M.; Weinand, M.E.; Oommen, K.J. Affective Self-Report during the Intracarotid Sodium Amobarbital Test. J. Clin. Exp. Neuropsychol. 1994, 16, 372–376. [Google Scholar] [CrossRef] [PubMed]
  48. Lee, G.P.; Loring, D.W.; Meader, K.J.; Brooks, B.B. Hemispheric Specialization for Emotional Expression: A Reexamination of Results from Lntracarotid Administration of Sodium Amobarbital. Brain Cogn. 1990, 12, 14. [Google Scholar] [CrossRef]
  49. Perria, L.; Rosadini, F.; Rossi, G. Determination of Side of Cerebral Dominance with Amobarbital. Arch. Neurol. 1961, 4, 173–181. [Google Scholar] [CrossRef]
  50. Gainotti, G. Emotional Behavior and Hemispheric Side of the Lesion. Cortex 1972, 8, 41–55. [Google Scholar] [CrossRef]
  51. Robinson, R.G.; Kubos, K.L.; Starr, L.B.; Rao, K.; Price, T.R. Mood Disorder in Stroke Patients: Importance of Location of Lesion. Brain 1984, 107, 81–93. [Google Scholar] [CrossRef]
  52. Sackeim, H.A.; Greenberg, M.S.; Weiman, A.L.; Gur, R.C.; Hungerbuhler, J.P.; Geschwind, N. Hemispheric Asymmetry in the Expression of Positive and Negative Emotions: Neurologic Evidence. Arch. Neurol. 1982, 39, 210–218. [Google Scholar] [CrossRef] [PubMed]
  53. George, M.S.; Kellner, C.H.; Bernstein, H.; Goust, J.M. A Magnetic Resonance Imaging Investigation into Mood Disorders in Multiple Sclerosis: A Pilot Study. J. Nerv. Ment. Dis. 1994, 182, 410–412. [Google Scholar] [CrossRef] [PubMed]
  54. Padmanabhan, J.L.; Cooke, D.; Joutsa, J.; Siddiqi, S.H.; Ferguson, M.; Darby, R.R.; Soussand, L.; Horn, A.; Kim, N.Y.; Voss, J.L.; et al. A Human Depression Circuit Derived From Focal Brain Lesions. Biol. Psychiatry 2019, 86, 749–758. [Google Scholar] [CrossRef] [PubMed]
  55. Zhang, J.; Kendrick, K.M.; Lu, G.; Feng, J. The Fault Lies on the Other Side: Altered Brain Functional Connectivity in Psychiatric Disorders Is Mainly Caused by Counterpart Regions in the Opposite Hemisphere. Cereb. Cortex 2015, 25, 3475–3486. [Google Scholar] [CrossRef] [PubMed]
  56. Hadidi, N.; Treat-Jacobson, D.J.; Lindquist, R. Poststroke Depression and Functional Outcome: A Critical Review of Literature. Heart Lung 2009, 38, 151–162. [Google Scholar] [CrossRef]
  57. Yu, L.; Liu, C.-K.; Chen, J.-W.; Wang, S.-Y.; Wu, Y.-H.; Yu, S.-H. Relationship Between Post-Stroke Depression and Lesion Location: A Meta-Analysis. Kaohsiung J. Med. Sci. 2004, 20, 372–380. [Google Scholar] [CrossRef] [Green Version]
  58. Wei, N.; Yong, W.; Li, X.; Zhou, Y.; Deng, M.; Zhu, H.; Jin, H. Post-Stroke Depression and Lesion Location: A Systematic Review. J. Neurol. 2015, 262, 81–90. [Google Scholar] [CrossRef]
  59. Zhang, Y.; Zhao, H.; Fang, Y.; Wang, S.; Zhou, H. The Association between Lesion Location, Sex and Poststroke Depression: Meta-Analysis. Brain Behav. 2017, 7, e00788. [Google Scholar] [CrossRef]
  60. Drysdale, A.T.; Grosenick, L.; Downar, J.; Dunlop, K.; Mansouri, F.; Meng, Y.; Fetcho, R.N.; Zebley, B.; Oathes, D.J.; Etkin, A.; et al. Resting-State Connectivity Biomarkers Define Neurophysiological Subtypes of Depression. Nat. Med. 2017, 23, 28–38. [Google Scholar] [CrossRef] [Green Version]
  61. Liston, C.; Chen, A.C.; Zebley, B.D.; Drysdale, A.T.; Gordon, R.; Leuchter, B.; Voss, H.U.; Casey, B.J.; Etkin, A.; Dubin, M.J. Default Mode Network Mechanisms of Transcranial Magnetic Stimulation in Depression. Biol. Psychiatry 2014, 76, 517–526. [Google Scholar] [CrossRef] [Green Version]
  62. Menon, V. Large-Scale Brain Networks and Psychopathology: A Unifying Triple Network Model. Trends Cogn. Sci. 2011, 15, 483–506. [Google Scholar] [CrossRef]
  63. Siddiqi, S.H.; Schaper, F.L.W.V.J.; Horn, A.; Hsu, J.; Padmanabhan, J.L.; Brodtmann, A.; Cash, R.F.H.; Corbetta, M.; Choi, K.S.; Dougherty, D.D.; et al. Brain Stimulation and Brain Lesions Converge on Common Causal Circuits in Neuropsychiatric Disease. Nat. Hum. Behav. 2021, 5, 1707–1716. [Google Scholar] [CrossRef] [PubMed]
  64. Duffau, H. New Philosophy, Clinical Pearls, and Methods for Intraoperative Cognition Mapping and Monitoring “à La Carte” in Brain Tumor Patients. Neurosurgery 2021, 88, 919–930. [Google Scholar] [CrossRef]
  65. Fox, K.C.R.; Shi, L.; Baek, S.; Raccah, O.; Foster, B.L.; Saha, S.; Margulies, D.S.; Kucyi, A.; Parvizi, J. Intrinsic Network Architecture Predicts the Effects Elicited by Intracranial Electrical Stimulation of the Human Brain. Nat. Hum. Behav. 2020, 4, 1039–1052. [Google Scholar] [CrossRef] [PubMed]
  66. Herbet, G.; Lafargue, G.; Bonnetblanc, F.; Moritz-Gasser, S.; Duffau, H. Is the Right Frontal Cortex Really Crucial in the Mentalizing Network? A Longitudinal Study in Patients with a Slow-Growing Lesion. Cortex 2013, 49, 2711–2727. [Google Scholar] [CrossRef]
  67. Herbet, G.; Lafargue, G.; Bonnetblanc, F.; Moritz-Gasser, S.; Menjot de Champfleur, N.; Duffau, H. Inferring a Dual-Stream Model of Mentalizing from Associative White Matter Fibres Disconnection. Brain 2014, 137, 944–959. [Google Scholar] [CrossRef]
  68. Giussani, C.; Pirillo, D.; Roux, F.-E. Mirror of the Soul: A Cortical Stimulation Study on Recognition of Facial Emotions: Clinical Article. J. Neurosurg. 2010, 112, 520–527. [Google Scholar] [CrossRef] [PubMed]
  69. Nakajima, R.; Kinoshita, M.; Okita, H.; Liu, Z.; Nakada, M. Preserving Right Pre-Motor and Posterior Prefrontal Cortices Contribute to Maintaining Overall Basic Emotion. Front. Hum. Neurosci. 2021, 15, 64. [Google Scholar] [CrossRef]
  70. Giussani, C.; Roux, F.-E.; Bello, L.; Lauwers-Cances, V.; Papagno, C.; Gaini, S.M.; Puel, M.; Démonet, J.-F. Who Is Who: Areas of the Brain Associated with Recognizing and Naming Famous Faces: Clinical Article. J. Neurosurg. 2009, 110, 289–299. [Google Scholar] [CrossRef] [Green Version]
  71. Fernández, L.; Santos, C.; Gómez, E.; Velásquez, C.; Martino, J. Eliciting Smiles and Laughter During Intraoperative Electric Stimulation of the Cingulum: Surgical Scenario. World Neurosurg. 2020, 133, 55. [Google Scholar] [CrossRef]
  72. Bijanki, K.R.; Manns, J.R.; Inman, C.S.; Choi, K.S.; Harati, S.; Pedersen, N.P.; Drane, D.L.; Waters, A.C.; Fasano, R.E.; Mayberg, H.S.; et al. Cingulum Stimulation Enhances Positive Affect and Anxiolysis to Facilitate Awake Craniotomy. J. Clin. Investig. 2019, 129, 1152–1166. [Google Scholar] [CrossRef] [Green Version]
  73. Mills, K.A. Probing the Happy Place. J. Clin. Investig. 2019, 129, 952–954. [Google Scholar] [CrossRef] [Green Version]
  74. Elias, G.J.B.; Germann, J.; Boutet, A.; Pancholi, A.; Beyn, M.E.; Bhatia, K.; Neudorfer, C.; Loh, A.; Rizvi, S.J.; Bhat, V.; et al. Structuro-Functional Surrogates of Response to Subcallosal Cingulate Deep Brain Stimulation for Depression. Brain 2021, awab284. [Google Scholar] [CrossRef]
  75. Cash, R.F.H.; Zalesky, A.; Thomson, R.H.; Tian, Y.; Cocchi, L.; Fitzgerald, P.B. Subgenual Functional Connectivity Predicts Antidepressant Treatment Response to Transcranial Magnetic Stimulation: Independent Validation and Evaluation of Personalization. Biol. Psychiatry 2019, 86, e5–e7. [Google Scholar] [CrossRef]
  76. Bryden, M. Laterality Functional Asymmetry in the Intact Brain; Elsevier: Amsterdam, The Netherlands, 1982; ISBN 978-032-315-542-7. [Google Scholar]
  77. Bruder, G.E.; Quitkin, F.M.; Stewart, J.W.; Martin, C.; Voglmaier, M.M.; Harrison, W.M. Cerebral Laterality and Depression: Differences in Perceptual Asymmetry among Diagnostic Subtypes. J. Abnorm. Psychol. 1989, 98, 177–186. [Google Scholar] [CrossRef]
  78. Bruder, G.E.; Wexler, B.E.; Stewart, J.W.; Price, L.H.; Quitkin, F.M. Perceptual Asymmetry Differences between Major Depression with or without a Comorbid Anxiety Disorder: A Dichotic Listening Study. J. Abnorm. Psychol. 1999, 108, 233–239. [Google Scholar] [CrossRef] [PubMed]
  79. Bruder, G.E.; Schneier, F.R.; Stewart, J.W.; McGrath, P.J.; Quitkin, F. Left Hemisphere Dysfunction During Verbal Dichotic Listening Tests in Patients Who Have Social Phobia With or Without Comorbid Depressive Disorder. Am. J. Psychiatry 2004, 161, 72–78. [Google Scholar] [CrossRef] [Green Version]
  80. Heller, W.; Etienne, M.A.; Miller, G.A. Patterns of Perceptual Asymmetry in Depression and Anxiety: Implications for Neuropsychological Models of Emotion and Psychopathology. J. Abnorm. Psychol. 1995, 104, 327–333. [Google Scholar] [CrossRef] [PubMed]
  81. Bruder, G.E.; Stewart, J.W.; McGrath, P.J.; Ma, G.J.; Wexler, B.E.; Quitkin, F.M. Atypical Depression: Enhanced Right Hemispheric Dominance for Perceiving Emotional Chimeric Faces. J. Abnorm. Psychol. 2002, 111, 446–454. [Google Scholar] [CrossRef] [PubMed]
  82. Gazzaniga, M.S.; LeDoux, J.E. The Integrated Mind; Springer Science & Business Media: Berlin/Heidelberg, Germany, 1978; ISBN 978-148-992-206-9. [Google Scholar]
  83. Benowitz, L.I.; Bear, D.M.; Rosenthal, R.; Mesulam, M.M.; Zaidel, E.; Sperry, R.W. Hemispheric Specialization in Nonverbal Communication. Cortex 1983, 19, 5–11. [Google Scholar] [CrossRef]
  84. Schmalhofer, F.; Perfetti, C.A. Higher Level Language Processes in the Brain: Inference and Comprehension Processes; Psychology Press: Hove, UK, 2007; ISBN 978-113-560-566-7. [Google Scholar]
  85. Paul, L.K.; Van Lancker-Sidtis, D.; Schieffer, B.; Dietrich, R.; Brown, W.S. Communicative Deficits in Agenesis of the Corpus Callosum: Nonliteral Language and Affective Prosody. Brain Lang. 2003, 85, 313–324. [Google Scholar] [CrossRef]
  86. Turk, A.A.; Brown, W.S.; Symington, M.; Paul, L.K. Social Narratives in Agenesis of the Corpus Callosum: Linguistic Analysis of the Thematic Apperception Test. Neuropsychologia 2010, 48, 43–50. [Google Scholar] [CrossRef]
  87. Baynes, K.; Gazzaniga, M.S. Consciousness, Introspection, and the Split-Brain: The Two Minds/One Body Problem. In The New Cognitive Neurosciences, 2nd ed.; Gazzaniga, M.S., Ed.; MIT Press: Cambridge, MA, USA, 2000. [Google Scholar]
  88. Gainotti, G. The Role of the Right Hemisphere in Emotional and Behavioral Disorders of Patients With Frontotemporal Lobar Degeneration: An Updated Review. Front. Aging Neurosci. 2019, 11, 55. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Cook, I.A.; O’Hara, R.; Uijtdehaage, S.H.J.; Mandelkern, M.; Leuchter, A.F. Assessing the Accuracy of Topographic EEG Mapping for Determining Local Brain Function. Electroencephalogr. Clin. Neurophysiol. 1998, 107, 408–414. [Google Scholar] [CrossRef]
  90. Nusslock, R.; Walden, K.; Harmon-Jones, E. Asymmetrical Frontal Cortical Activity Associated with Differential Risk for Mood and Anxiety Disorder Symptoms: An RDoC Perspective. Int. J. Psychophysiol. 2015, 98, 249–261. [Google Scholar] [CrossRef]
  91. Harmon-Jones, E.; Allen, J.J.B. Behavioral Activation Sensitivity and Resting Frontal EEG Asymmetry: Covariation of Putative Indicators Related to Risk for Mood Disorders. J. Abnorm. Psychol. 1997, 106, 159–163. [Google Scholar] [CrossRef] [PubMed]
  92. Van der Vinne, N.; Vollebregt, M.A.; van Putten, M.J.A.M.; Arns, M. Frontal Alpha Asymmetry as a Diagnostic Marker in Depression: Fact or Fiction? A Meta-Analysis. NeuroImage Clin. 2017, 16, 79–87. [Google Scholar] [CrossRef]
  93. Grimshaw, G.M.; Carmel, D. An Asymmetric Inhibition Model of Hemispheric Differences in Emotional Processing. Front. Psychol. 2014, 5, 498. [Google Scholar] [CrossRef]
  94. Arns, M.; Bruder, G.; Hegerl, U.; Spooner, C.; Palmer, D.M.; Etkin, A.; Fallahpour, K.; Gatt, J.M.; Hirshberg, L.; Gordon, E. EEG Alpha Asymmetry as a Gender-Specific Predictor of Outcome to Acute Treatment with Different Antidepressant Medications in the Randomized ISPOT-D Study. Clin. Neurophysiol. 2016, 127, 509–519. [Google Scholar] [CrossRef]
  95. Kołodziej, A.; Magnuski, M.; Ruban, A.; Brzezicka, A. No Relationship between Frontal Alpha Asymmetry and Depressive Disorders in a Multiverse Analysis of Five Studies. eLife 2021, 10, e60595. [Google Scholar] [CrossRef]
  96. Van Tol, M.-J.; van der Wee, N.J.A.; van den Heuvel, O.A.; Nielen, M.M.A.; Demenescu, L.R.; Aleman, A.; Renken, R.; van Buchem, M.A.; Zitman, F.G.; Veltman, D.J. Regional Brain Volume in Depression and Anxiety Disorders. Arch. Gen. Psychiatry 2010, 67, 1002–1011. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Bora, E.; Fornito, A.; Pantelis, C.; Yücel, M. Gray Matter Abnormalities in Major Depressive Disorder: A Meta-Analysis of Voxel Based Morphometry Studies. J. Affect. Disord. 2012, 138, 9–18. [Google Scholar] [CrossRef] [PubMed]
  98. Peng, W.; Jia, Z.; Huang, X.; Lui, S.; Kuang, W.; Sweeney, J.A.; Gong, Q. Brain Structural Abnormalities in Emotional Regulation and Sensory Processing Regions Associated with Anxious Depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2019, 94, 109676. [Google Scholar] [CrossRef] [PubMed]
  99. Canu, E.; Kostić, M.; Agosta, F.; Munjiza, A.; Ferraro, P.M.; Pesic, D.; Copetti, M.; Peljto, A.; Tosevski, D.L.; Filippi, M. Brain Structural Abnormalities in Patients with Major Depression with or without Generalized Anxiety Disorder Comorbidity. J. Neurol. 2015, 262, 1255–1265. [Google Scholar] [CrossRef]
  100. Liu, J.; Xu, X.; Luo, Q.; Luo, Y.; Chen, Y.; Lui, S.; Wu, M.; Zhu, H.; Kemp, G.J.; Gong, Q. Brain Grey Matter Volume Alterations Associated with Antidepressant Response in Major Depressive Disorder. Sci. Rep. 2017, 7, 10464. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Boes, A.D.; Uitermarkt, B.D.; Albazron, F.M.; Lan, M.J.; Liston, C.; Pascual-Leone, A.; Dubin, M.J.; Fox, M.D. Rostral Anterior Cingulate Cortex Is a Structural Correlate of Repetitive TMS Treatment Response in Depression. Brain Stimul. 2018, 11, 575–581. [Google Scholar] [CrossRef]
  102. Lan, M.J.; Chhetry, B.T.; Liston, C.; Mann, J.J.; Dubin, M. Transcranial Magnetic Stimulation of Left Dorsolateral Prefrontal Cortex Induces Brain Morphological Changes in Regions Associated with a Treatment Resistant Major Depressive Episode: An Exploratory Analysis. Brain Stimul. 2016, 9, 577–583. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Holroyd, C.B.; Umemoto, A. The Research Domain Criteria Framework: The Case for Anterior Cingulate Cortex. Neurosci. Biobehav. Rev. 2016, 71, 418–443. [Google Scholar] [CrossRef]
  104. Dalhuisen, I.; Ackermans, E.; Martens, L.; Mulders, P.; Bartholomeus, J.; de Bruijn, A.; Spijker, J.; van Eijndhoven, P.; Tendolkar, I. Longitudinal Effects of RTMS on Neuroplasticity in Chronic Treatment-Resistant Depression. Eur. Arch. Psychiatry Clin. Neurosci. 2021, 271, 39–47. [Google Scholar] [CrossRef] [PubMed]
  105. Albert, P.R. Adult Neuroplasticity: A New “Cure” for Major Depression? J. Psychiatry Neurosci. 2019, 44, 147–150. [Google Scholar] [CrossRef]
  106. Bench, C.J.; Friston, K.J.; Brown, R.G.; Scott, L.C.; Frackowiak, R.S.J.; Dolan, R.J. The Anatomy of Melancholia—Focal Abnormalities of Cerebral Blood Flow in Major Depression. Psychol. Med. 1992, 22, 607–615. [Google Scholar] [CrossRef] [Green Version]
  107. Baxter, L.R., Jr.; Phelps, M.E.; Mazziotta, J.C.; Schwartz, J.M.; Gerner, R.H.; Selin, C.E.; Sumida, R.M. Cerebral Metabolic Rates for Glucose in Mood Disorders: Studies With Positron Emission Tomography and Fluorodeoxyglucose F 18. Arch. Gen. Psychiatry 1985, 42, 441–447. [Google Scholar] [CrossRef]
  108. Martinot, J.-L.; Hardy, P.; Feline, A.; Huret, J.-D.; Mazoyer, B.; Attar-Levy, D.; Pappata, S.; Syrota, A. Left Prefrontal Glucose Hypometabolism in the Depressed State: A Confirmation. Am. J. Psychiatry 1990, 147, 1313–1317. [Google Scholar] [CrossRef]
  109. Fitzgerald, P.B.; Oxley, T.J.; Laird, A.R.; Kulkarni, J.; Egan, G.F.; Daskalakis, Z.J. An Analysis of Functional Neuroimaging Studies of Dorsolateral Prefrontal Cortical Activity in Depression. Psychiatry Res. Neuroimaging 2006, 148, 33–45. [Google Scholar] [CrossRef]
  110. Hamilton, J.P.; Etkin, A.; Furman, D.J.; Lemus, M.G.; Johnson, R.F.; Gotlib, I.H. Functional Neuroimaging of Major Depressive Disorder: A Meta-Analysis and New Integration of Baseline Activation and Neural Response Data. Am. J. Psychiatry 2012, 169, 693–703. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Herwig, U.; Lampe, Y.; Juengling, F.D.; Wunderlich, A.; Walter, H.; Spitzer, M.; Schönfeldt-Lecuona, C. Add-on RTMS for Treatment of Depression: A Pilot Study Using Stereotaxic Coil-Navigation According to PET Data. J. Psychiatr. Res. 2003, 37, 267–275. [Google Scholar] [CrossRef]
  112. Padberg, F.; George, M.S. Repetitive Transcranial Magnetic Stimulation of the Prefrontal Cortex in Depression. Exp. Neurol. 2009, 219, 2–13. [Google Scholar] [CrossRef] [PubMed]
  113. Paillère Martinot, M.-L.; Galinowski, A.; Ringuenet, D.; Gallarda, T.; Lefaucheur, J.-P.; Bellivier, F.; Picq, C.; Bruguière, P.; Mangin, J.-F.; Rivière, D.; et al. Influence of Prefrontal Target Region on the Efficacy of Repetitive Transcranial Magnetic Stimulation in Patients with Medication-Resistant Depression: A [18F]-Fluorodeoxyglucose PET and MRI Study. Int. J. Neuropsychopharmacol. 2010, 13, 45–59. [Google Scholar] [CrossRef] [Green Version]
  114. Fountoulakis, K.N.; Iacovides, A.; Gerasimou, G.; Fotiou, F.; Ioannidou, C.; Bascialla, F.; Grammaticos, P.; Kaprinis, G. The Relationship of Regional Cerebral Blood Flow with Subtypes of Major Depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2004, 28, 537–546. [Google Scholar] [CrossRef]
  115. Liao, Y.; Huang, X.; Wu, Q.; Yang, C.; Kuang, W.; Du, M.; Lui, S.; Yue, Q.; Chan, R.C.K.; Kemp, G.J.; et al. Is Depression a Disconnection Syndrome? Meta-Analysis of Diffusion Tensor Imaging Studies in Patients with MDD. J. Psychiatry Neurosci. 2013, 38, 49–56. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Schnyer, D.M.; Clasen, P.C.; Gonzalez, C.; Beevers, C.G. Evaluating the Diagnostic Utility of Applying a Machine Learning Algorithm to Diffusion Tensor MRI Measures in Individuals with Major Depressive Disorder. Psychiatry Res. Neuroimaging 2017, 264, 1–9. [Google Scholar] [CrossRef] [PubMed]
  117. Chen, G.; Hu, X.; Li, L.; Huang, X.; Lui, S.; Kuang, W.; Ai, H.; Bi, F.; Gu, Z.; Gong, Q. Disorganization of White Matter Architecture in Major Depressive Disorder: A Meta-Analysis of Diffusion Tensor Imaging with Tract-Based Spatial Statistics. Sci. Rep. 2016, 6, 21825. [Google Scholar] [CrossRef] [PubMed]
  118. Hermesdorf, M.; Sundermann, B.; Feder, S.; Schwindt, W.; Minnerup, J.; Arolt, V.; Berger, K.; Pfleiderer, B.; Wersching, H. Major Depressive Disorder: Findings of Reduced Homotopic Connectivity and Investigation of Underlying Structural Mechanisms. Hum. Brain Mapp. 2016, 37, 1209–1217. [Google Scholar] [CrossRef]
  119. Jiang, J.; Zhao, Y.-J.; Hu, X.-Y.; Du, M.-Y.; Chen, Z.-Q.; Wu, M.; Li, K.-M.; Zhu, H.-Y.; Kumar, P.; Gong, Q.-Y. Microstructural Brain Abnormalities in Medication-Free Patients with Major Depressive Disorder: A Systematic Review and Meta-Analysis of Diffusion Tensor Imaging. J. Psychiatry Neurosci. 2017, 42, 150–163. [Google Scholar] [CrossRef] [Green Version]
  120. Jiang, X.; Shen, Y.; Yao, J.; Zhang, L.; Xu, L.; Feng, R.; Cai, L.; Liu, J.; Chen, W.; Wang, J. Connectome Analysis of Functional and Structural Hemispheric Brain Networks in Major Depressive Disorder. Transl. Psychiatry 2019, 9, 136. [Google Scholar] [CrossRef] [Green Version]
  121. Kozel, F.A.; Johnson, K.A.; Nahas, Z.; Nakonezny, P.A.; Morgan, P.S.; Anderson, B.S.; Kose, S.; Li, X.; Lim, K.O.; Trivedi, M.H.; et al. Fractional Anisotropy Changes After Several Weeks of Daily Left High-Frequency Repetitive Transcranial Magnetic Stimulation of the Prefrontal Cortex to Treat Major Depression. J. ECT 2011, 27, 5–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Peng, H.; Zheng, H.; Li, L.; Liu, J.; Zhang, Y.; Shan, B.; Zhang, L.; Yin, Y.; Liu, J.; Li, W.; et al. High-Frequency RTMS Treatment Increases White Matter FA in the Left Middle Frontal Gyrus in Young Patients with Treatment-Resistant Depression. J. Affect. Disord. 2012, 136, 249–257. [Google Scholar] [CrossRef]
  123. Barredo, J.; Bellone, J.A.; Edwards, M.; Carpenter, L.L.; Correia, S.; Philip, N.S. White Matter Integrity and Functional Predictors of Response to Repetitive Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder and Major Depression. Depress. Anxiety 2019, 36, 1047–1057. [Google Scholar] [CrossRef] [PubMed]
  124. Raij, T.; Nummenmaa, A.; Marin, M.-F.; Porter, D.; Furtak, S.; Setsompop, K.; Milad, M.R. Prefrontal Cortex Stimulation Enhances Fear Extinction Memory in Humans. Biol. Psychiatry 2018, 84, 129–137. [Google Scholar] [CrossRef]
  125. Tao, Q.; Yang, Y.; Yu, H.; Fan, L.; Luan, S.; Zhang, L.; Zhao, H.; Lv, L.; Jiang, T.; Song, X. Anatomical Connectivity-Based Strategy for Targeting Transcranial Magnetic Stimulation as Antidepressant Therapy. Front. Psychiatry 2020, 11, 236. [Google Scholar] [CrossRef]
  126. Alexopoulos, G.S. Frontostriatal and Limbic Dysfunction in Late-Life Depression. Am. J. Geriatr. Psychiatry 2002, 10, 687–695. [Google Scholar] [CrossRef]
  127. Diener, C.; Kuehner, C.; Brusniak, W.; Ubl, B.; Wessa, M.; Flor, H. A Meta-Analysis of Neurofunctional Imaging Studies of Emotion and Cognition in Major Depression. NeuroImage 2012, 61, 677–685. [Google Scholar] [CrossRef]
  128. Lawrence, N.S.; Williams, A.M.; Surguladze, S.; Giampietro, V.; Brammer, M.J.; Andrew, C.; Frangou, S.; Ecker, C.; Phillips, M.L. Subcortical and Ventral Prefrontal Cortical Neural Responses to Facial Expressions Distinguish Patients with Bipolar Disorder and Major Depression. Biol. Psychiatry 2004, 55, 578–587. [Google Scholar] [CrossRef]
  129. Siegle, G.J.; Steinhauer, S.R.; Thase, M.E.; Stenger, V.A.; Carter, C.S. Can’t Shake That Feeling: Event-Related FMRI Assessment of Sustained Amygdala Activity in Response to Emotional Information in Depressed Individuals. Biol. Psychiatry 2002, 51, 693–707. [Google Scholar] [CrossRef]
  130. Elliott, R.; Rubinsztein, J.S.; Sahakian, B.J.; Dolan, R.J. The Neural Basis of Mood-Congruent Processing Biases in Depression. Arch. Gen. Psychiatry 2002, 59, 597–604. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  131. Kumari, V.; Mitterschiffthaler, M.T.; Teasdale, J.D.; Malhi, G.S.; Brown, R.G.; Giampietro, V.; Brammer, M.J.; Poon, L.; Simmons, A.; Williams, S.C.R.; et al. Neural Abnormalities during Cognitive Generation of Affect in Treatment-Resistant Depression. Biol. Psychiatry 2003, 54, 777–791. [Google Scholar] [CrossRef]
  132. Müller, V.I.; Cieslik, E.C.; Serbanescu, I.; Laird, A.R.; Fox, P.T.; Eickhoff, S.B. Altered Brain Activity in Unipolar Depression Revisited: Meta-Analyses of Neuroimaging Studies. JAMA Psychiatry 2017, 74, 47–55. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Engels, A.S.; Heller, W.; Spielberg, J.M.; Warren, S.L.; Sutton, B.P.; Banich, M.T.; Miller, G.A. Co-Occurring Anxiety Influences Patterns of Brain Activity in Depression. Cogn. Affect. Behav. Neurosci. 2010, 10, 141–156. [Google Scholar] [CrossRef] [Green Version]
  134. Drevets, W.C.; Savitz, J.; Trimble, M. The Subgenual Anterior Cingulate Cortex in Mood Disorders. CNS Spectr. 2008, 13, 663–681. [Google Scholar] [CrossRef] [PubMed]
  135. Mayberg, H.S. Defining the Neural Circuitry of Depression: Toward a New Nosology With Therapeutic Implications. Biol. Psychiatry 2007, 61, 729–730. [Google Scholar] [CrossRef]
  136. Fox, M.D.; Buckner, R.L.; White, M.P.; Greicius, M.D.; Pascual-Leone, A. Efficacy of Transcranial Magnetic Stimulation Targets for Depression Is Related to Intrinsic Functional Connectivity with the Subgenual Cingulate. Biol. Psychiatry 2012, 72, 595–603. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Cole, E.J.; Phillips, A.L.; Bentzley, B.S.; Stimpson, K.H.; Nejad, R.; Barmak, F.; Veerapal, C.; Khan, N.; Cherian, K.; Felber, E.; et al. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. Am. J. Psychiatry 2021. (Online ahead of print). [Google Scholar] [CrossRef]
  138. Cole, E.J.; Stimpson, K.H.; Bentzley, B.S.; Gulser, M.; Cherian, K.; Tischler, C.; Nejad, R.; Pankow, H.; Choi, E.; Aaron, H.; et al. Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. Am. J. Psychiatry 2020, 177, 716–726. [Google Scholar] [CrossRef] [PubMed]
  139. Siddiqi, S.H.; Trapp, N.T.; Hacker, C.D.; Laumann, T.O.; Kandala, S.; Hong, X.; Trillo, L.; Shahim, P.; Leuthardt, E.C.; Carter, A.R.; et al. Repetitive Transcranial Magnetic Stimulation with Resting-State Network Targeting for Treatment-Resistant Depression in Traumatic Brain Injury: A Randomized, Controlled, Double-Blinded Pilot Study. J. Neurotrauma 2018, 36, 1361–1374. [Google Scholar] [CrossRef]
  140. Williams, N.R.; Sudheimer, K.D.; Bentzley, B.S.; Pannu, J.; Stimpson, K.H.; Duvio, D.; Cherian, K.; Hawkins, J.; Scherrer, K.H.; Vyssoki, B.; et al. High-Dose Spaced Theta-Burst TMS as a Rapid-Acting Antidepressant in Highly Refractory Depression. Brain 2018, 141, e18. [Google Scholar] [CrossRef]
  141. Fried, E.I.; Nesse, R.M. Depression Is Not a Consistent Syndrome: An Investigation of Unique Symptom Patterns in the STAR*D Study. J. Affect. Disord. 2015, 172, 96–102. [Google Scholar] [CrossRef] [Green Version]
  142. Quinn, D.K.; Jones, T.R.; Upston, J.; Huff, M.; Ryman, S.G.; Vakhtin, A.A.; Abbott, C.C. Right Prefrontal Intermittent Theta-Burst Stimulation for Major Depressive Disorder: A Case Series. Brain Stimul. Basic Transl. Clin. Res. Neuromodulation 2021, 14, 97–99. [Google Scholar] [CrossRef]
  143. Pannekoek, J.N.; van der Werff, S.J.A.; van Tol, M.J.; Veltman, D.J.; Aleman, A.; Zitman, F.G.; Rombouts, S.A.R.B.; van der Wee, N.J.A. Investigating Distinct and Common Abnormalities of Resting-State Functional Connectivity in Depression, Anxiety, and Their Comorbid States. Eur. Neuropsychopharmacol. 2015, 25, 1933–1942. [Google Scholar] [CrossRef]
  144. Price, R.B.; Gates, K.; Kraynak, T.E.; Thase, M.E.; Siegle, G.J. Data-Driven Subgroups in Depression Derived from Directed Functional Connectivity Paths at Rest. Neuropsychopharmacology 2017, 42, 2623–2632. [Google Scholar] [CrossRef] [PubMed]
  145. Siddiqi, S.H.; Taylor, S.F.; Cooke, D.; Pascual-Leone, A.; George, M.S.; Fox, M.D. Distinct Symptom-Specific Treatment Targets for Circuit-Based Neuromodulation. Am. J. Psychiatry 2020, 177, 435–446. [Google Scholar] [CrossRef]
  146. Baeken, C.; De Raedt, R.; Van Schuerbeek, P.; Vanderhasselt, M.A.; De Mey, J.; Bossuyt, A.; Luypaert, R. Right Prefrontal HF-RTMS Attenuates Right Amygdala Processing of Negatively Valenced Emotional Stimuli in Healthy Females. Behav. Brain Res. 2010, 214, 450–455. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Chen, A.C.; Oathes, D.J.; Chang, C.; Bradley, T.; Zhou, Z.-W.; Williams, L.M.; Glover, G.H.; Deisseroth, K.; Etkin, A. Causal Interactions between Fronto-Parietal Central Executive and Default-Mode Networks in Humans. Proc. Natl. Acad. Sci. USA 2013, 110, 19944–19949. [Google Scholar] [CrossRef] [Green Version]
  148. Shao, R.; Lau, W.K.W.; Leung, M.-K.; Lee, T.M.C. Subgenual Anterior Cingulate-Insula Resting-State Connectivity as a Neural Correlate to Trait and State Stress Resilience. Brain Cogn. 2018, 124, 73–81. [Google Scholar] [CrossRef]
  149. Uddin, L.Q. Salience Processing and Insular Cortical Function and Dysfunction. Nat. Rev. Neurosci. 2015, 16, 55–61. [Google Scholar] [CrossRef] [PubMed]
  150. Beynel, L.; Powers, J.P.; Appelbaum, L.G. Effects of Repetitive Transcranial Magnetic Stimulation on Resting-State Connectivity: A Systematic Review. NeuroImage 2020, 211, 116596. [Google Scholar] [CrossRef] [PubMed]
  151. Philip, N.S.; Barredo, J.; Aiken, E.; Carpenter, L.L. Neuroimaging Mechanisms of Therapeutic Transcranial Magnetic Stimulation for Major Depressive Disorder. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 2018, 3, 211–222. [Google Scholar] [CrossRef]
  152. Kozel, F.A.; Van Trees, K.; Larson, V.; Phillips, S.; Hashimie, J.; Gadbois, B.; Johnson, S.; Gallinati, J.; Barrett, B.; Toyinbo, P.; et al. One Hertz versus Ten Hertz Repetitive TMS Treatment of PTSD: A Randomized Clinical Trial. Psychiatry Res. 2019, 273, 153–162. [Google Scholar] [CrossRef] [PubMed]
  153. Philip, N.S.; Barredo, J.; Aiken, E.; Larson, V.; Jones, R.N.; Shea, M.T.; Greenberg, B.D.; van ’t Wout-Frank, M. Theta-Burst Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder. Am. J. Psychiatry 2019, 176, 939–948. [Google Scholar] [CrossRef]
  154. Sarkhel, S.; Sinha, V.K.; Praharaj, S.K. Adjunctive High-Frequency Right Prefrontal Repetitive Transcranial Magnetic Stimulation (RTMS) Was Not Effective in Obsessive–Compulsive Disorder but Improved Secondary Depression. J. Anxiety Disord. 2010, 24, 535–539. [Google Scholar] [CrossRef] [PubMed]
  155. Cirillo, P.; Gold, A.K.; Nardi, A.E.; Ornelas, A.C.; Nierenberg, A.A.; Camprodon, J.; Kinrys, G. Transcranial Magnetic Stimulation in Anxiety and Trauma-Related Disorders: A Systematic Review and Meta-Analysis. Brain Behav. 2019, 9, e01284. [Google Scholar] [CrossRef] [PubMed]
  156. Kozel, F.A. Clinical Repetitive Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder, Generalized Anxiety Disorder, and Bipolar Disorder. Psychiatr. Clin. North Am. 2018, 41, 433–446. [Google Scholar] [CrossRef] [PubMed]
  157. Mantovani, A.; Lisanby, S.H.; Pieraccini, F.; Ulivelli, M.; Castrogiovanni, P.; Rossi, S. Repetitive Transcranial Magnetic Stimulation (RTMS) in the Treatment of Panic Disorder (PD) with Comorbid Major Depression. J. Affect. Disord. 2007, 102, 277–280. [Google Scholar] [CrossRef] [PubMed]
  158. Cabeza, R.; Dennis, N.A. Frontal Lobes and Aging. In Principles of Frontal Lobe Function; Stuss, D.T., Knight, R.T., Eds.; Oxford University Press: Oxford, UK, 2013; pp. 628–652. ISBN 978-019-983-775-5. [Google Scholar]
Table
Table 1. Brief summary of findings.
Table 1. Brief summary of findings.
ParadigmDifferenceEffect
Sodium amobarbital injectionInjection into the left versus right carotid arteryInactivation of the left hemisphere led to temporary depression, while inactivation of the right hemisphere led to temporary euphoria [47,48,49]
Lesion StudiesLesions occurring in the anterior right versus left hemisphereA higher likelihood of depression observed following damage to the left hemisphere in contrast to an elevated mood following damage to the right hemisphere [50,51,52]
Lesion StudiesTime following strokeLesioning of the right hemisphere only associated with depression in the months following stroke [57,58]
Lesion StudiesIndividual moderating factorsWhether or not a lesion location is associated with depression dependent upon moderating factors like sex [59]
Lesion StudiesFunctional connectivity of lesion locationFunctional connectivity changes that accompany lesions are more important for depression than lesion location in either hemisphere [54]
Interoperative Brain StimulationEmotional processing versus affective experienceRight hemisphere strongly associated with identification of emotions in others [69,70]
Dichotic ListeningAdvantages in processing auditory stimuli associated with the right or left hemisphereThose with depression have worse performance processing non-verbal stimuli, while those with anxiety have worse performance processing verbal stimuli [77,78,79]
Perceptual AsymmetryHemi-spatial bias to visual stimuli presented to the right or left hemisphereA right hemisphere bias is seen in those with depression and dysthymia but not in those with depression and melancholia [81]
Split Brain PatientsPresentation to the right or left hemisphere visual field onlyAttributions for emotional changes brought on by viewing emotionally salient images only correct when seen through right hemisphere visual field [82]
Frontal Alpha AsymmetryEEG activity in right and left frontal lobesReduced activity in the left PFC seen in those diagnosed with MDD, compared to reduced activity in the right PFC in those with anxious apprehension [30,89,90]
Frontal Alpha AsymmetryEEG activity in right and left frontal lobes in older adults diagnosed with MDDIn females over the age of 53 diagnosed with MDD, hyperactivity of the left PFC was associated with depression, compared to hyperactivity of the right PFC in men over 53 [92]
Volumetric StudiesPFC brain volume in those with MDD with or without comorbid anxietyThose with MDD only had reduced brain volume in the right PFC; but the opposite finding has also been observed [96,97,99]
Volumetric StudiesBrain volume changes following antidepressant medication treatmentResponders to treatment had increases in grey matter compared to controls while non responders had decreases [100]
Volumetric StudiesBrain volume changes following rTMS treatmentIncreases in anterior cingulate cortex volume following rTMS associated with symptom improvement, though increases in volume also observed in the absence of clinical benefit [101,102,104]
Positron Emission TomographyDifferences in metabolism in the left PFCImpaired metabolism observed in the left PFC in those with MDD and improvements in metabolism associated with positive treatment outcomes [106,107,108]
Positron Emission TomographyDifferences in metabolism in the right PFCBoth hypo and hyper activity seen in those with MDD [109,110]
Positron Emission TomographyDifferences in PFC metabolism guiding rTMS placementWhile the right PFC was more often selected for treatment based on hypometabolism, this method did not lead to improved outcomes [111,113]
White Matter StudiesDifferences in white matter integrity between left and right hemispheres in those with MDDThose with MDD have more widespread white matter disruptions in right hemisphere compared to left, right hemisphere differences alone successful in correctly identifying those with MDD with 80% accuracy [115,116]
White matter studiesDifferences in white matter integrity in the corpus callosum in those with MDD versus controlsThose with MDD may have impaired interhemispheric communication [116,117]
Task Based fMRIDifferences in BOLD in the right and left PFC in those with MDDSome studies have identified a pattern of hypoactivity in the left PFC and hyperactivity in the right in those with MDD during an emotion induction task, while others have identified a hypoactive right PFC in those with MDD in the same task [127,128,129,130,131]
Functional ConnectivityIndividual moderating factorsFactors such as comorbid anxiety and sex may change connectivity patterns to bias right hemisphere treatment targets in rTMS [60,143,144]
Functional ConnectivityA matter of networks rather than hemispheresDifferences in cross hemispheric networks are more important in MDD than hemispheric location [63]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Gibson, B.C.; Vakhtin, A.; Clark, V.P.; Abbott, C.C.; Quinn, D.K. Revisiting Hemispheric Asymmetry in Mood Regulation: Implications for rTMS for Major Depressive Disorder. Brain Sci. 2022, 12, 112. https://doi.org/10.3390/brainsci12010112

AMA Style

Gibson BC, Vakhtin A, Clark VP, Abbott CC, Quinn DK. Revisiting Hemispheric Asymmetry in Mood Regulation: Implications for rTMS for Major Depressive Disorder. Brain Sciences. 2022; 12(1):112. https://doi.org/10.3390/brainsci12010112

Chicago/Turabian Style

Gibson, Benjamin C., Andrei Vakhtin, Vincent P. Clark, Christopher C. Abbott, and Davin K. Quinn. 2022. "Revisiting Hemispheric Asymmetry in Mood Regulation: Implications for rTMS for Major Depressive Disorder" Brain Sciences 12, no. 1: 112. https://doi.org/10.3390/brainsci12010112

APA Style

Gibson, B. C., Vakhtin, A., Clark, V. P., Abbott, C. C., & Quinn, D. K. (2022). Revisiting Hemispheric Asymmetry in Mood Regulation: Implications for rTMS for Major Depressive Disorder. Brain Sciences, 12(1), 112. https://doi.org/10.3390/brainsci12010112

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop